Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[O:23][CH2:24][CH2:25][CH3:26])/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[N:6][C:5]=2[N:4]([CH2:27][CH2:28][CH3:29])[N:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[O:23][CH2:24][CH2:25][CH3:26])/[CH:15]=[CH:16]/[C:17]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:18])=[N:6][C:5]=2[N:4]([CH2:27][CH2:28][CH3:29])[N:3]=1
Reactant: C1COCCN1
Reactant: CCCOc1ccc(/C=C/C(=O)O)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CCCOc1ccc(/C=C/C(=O)N2CCOCC2)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.6 %

Procedure:
To a stirred solution of (E)-3-(3-methyl-4-oxo-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-n-propoxycinnamic acid (Example 13; 1.0 g, 0.0025 mol) and morpholine (0.21 g, 0.0025 mol) in dichloromethane at 0° C. was added, sequentially, N-methylmorpholine (0.5 g, 0.005 mol), 1-hydroxybenzotriazole hydrate (0.383 g, 0.0025 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.957 g, 0.005 mol). The reaction mixture was allowed to warm to room temperature, stirred for 20 hours and evaporated under vacuum, then the residue partitioned between water (30 ml) and dichloromethane (30 ml). The organic phase was removed and the aqueous phase extracted with more dichloromethane (2×30 ml); the combined organic solutions were then dried (Na2SO4 and the solvent removed under vacuum to give a white solid. Purification by column chromatography (SiO2, CH2Cl2 then 3% MeOH in CH2Cl2) and crystallisation from ethyl acetate-hexane-methanol afforded the title compound as white crystals (0.74 g, 63%), m.p. 156-157° C. Found: C, 64.60; H, 6.85; N, 15.16. C25H31N5O4 requires C, 64.50; H,, 6.71; N, 15.04%.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([CH2:39][CH:40]2[CH2:44][C:43]3[CH:45]=[CH:46][CH:47]=[CH:48][C:42]=3[O:41]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([CH2:39][CH:40]2[CH2:44][C:43]3[CH:45]=[CH:46][CH:47]=[CH:48][C:42]=3[O:41]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(CC2Cc3ccccc3O2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC2Cc3ccccc3O2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 7.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.04 g), sodium hydrogen carbonate (1.49 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-2-ylmethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.86 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.05 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.07 g, 7%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:17]=[CH:16][C:6]([CH:7]=[N:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH2:14][CH3:15])=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:31])[C:21]1[CH:30]=[CH:29][C:24]([C:25](=[O:28])[CH2:26][Br:27])=[CH:23][CH:22]=1>>[Br-:27].[CH3:31][N:20]([CH3:19])[C:21]1[CH:30]=[CH:29][C:24]([C:25](=[O:28])[CH2:26][N:11]2[CH:12]=[CH:13][N+:9]([N:8]=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:18])=[CH:17][CH:16]=3)=[C:10]2[CH2:14][CH3:15])=[CH:23][CH:22]=1
Reactant: CCc1nccn1N=Cc1ccc(N(C)C)cc1
Reactant: CN(C)c1ccc(C(=O)CBr)cc1
Product: CCc1n(CC(=O)c2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Product: [Br-]
Reaction time: 0.5 h

Procedure:
A solution of 2.42 g (10 mmol) of 1-[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazole is treated with 2.42 g (10 mmol) of p-dimethylaminophenacyl bromide. After stirring at 40° for 30 minutes the product is crystallized out by the addition of ether and recrystallized from methylene chloride/ether. There is obtained 3-[p-(dimethylamino)phenacyl]-1-[[p-(dimethylamino)benzylidene]-amino]-2-ethylimidazolium bromide of melting point 247°.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:21](=O)[CH2:22][C:23](=O)[CH3:24])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.Cl.Cl.[CH2:51]([NH:58][NH2:59])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:21]1[N:58]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:59]=[C:23]([CH3:24])[CH:22]=1)=[O:4]
Reactant: NNCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)CC(C)=O
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1c1cc(C)nn1Cc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 375b) was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and benzylhydrazine dihydrochloride (CAS Reg. No. 20570-96-1) to give the title compound as yellow oil. MS (ESI): m/z=492.3 [M+H]+.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:14]=[C:15]([C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][C:18]=1[Cl:19]>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([CH3:8])[CH2:21][O:22]2)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccc(Cl)c(Cl)c2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(3,4-dichlorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[Al+3].[Cl-].[Cl-].[Cl-].[Cl-].C(C1NC=C[N+]=1C)C.Cl[C:26](=[O:31])[C:27]([O:29]C)=[O:28]>O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([F:1])=[C:3]2[C:11]([C:26](=[O:31])[C:27]([OH:29])=[O:28])=[CH:10][NH:9][C:4]=12
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1ncc(F)c2cc[nH]c12
Agent: CCc1[nH]cc[n+]1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Nc1ncc(F)c2c(C(=O)C(=O)O)c[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-fluoro-1H-pyrrolo[2,3-c]pyridin-7-amine (2.26 g, 15 mmol) was added to a mixture of AlCl3 (12.0 g, 90.0 mmol) and ethylmethylimidazolium chloride (4.38 g, 30.0 mmol). Methyl chlorooxoacetate (3.6 mL, 30.0 mmol) was added slowly to the above solution and the mixture was stirred at rt for 3 h. Reaction flask was placed in an ice bath and water was slowly added until a white precipitate formed. The solid was collected by filtration and suspended in DMF. TEA (7 mL) was added and the mixture was stirred at rt for 1 h. Solvent was removed in vacuum. Chloroform (50 mL) was added and the solid was collected by filtration to afford 2-(7-amino-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid as a bright yellow solid (2.3g, 90% pure). LCMS: m/e 238 (M+H)+, ret time 0.96 min (method 3).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:21][C:22](NC2C=CC(OC3C=CN=CC=3)=CC=2)=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]1[CH:44]=[C:43]([O:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=2)[CH:42]=[CH:41][C:40]=1[NH2:53]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:21][C:22]([NH:53][C:40]2[CH:41]=[CH:42][C:43]([O:45][C:46]3[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=3)=[CH:44][C:39]=2[F:38])=[O:23])[N:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: COCCOc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Product: COCCOc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C)c3)cc2F)cc1

Procedure:
The title compound was prepared in the same manner as described for 1-{5-tert-butyl-2-[4-(2-methoxyethoxy)phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]urea, replacing 4-(pyridin-4-yloxy)phenylamine with 2-fluoro-4-(2-methyl-pyridin-4-yloxy)phenyl-amine. 1H-NMR (DMSO-d6) δ 8.96 (s, 1H), 8.74 (s, 1H), 8.29 (d, J=6.0 Hz, 1H), 8.14 (t, J=9.3 Hz, 1H), 7.38 (d, J=9.0 Hz, 2H), 7.18 (d, J=9.0 Hz, 1H), 7.08 (dd, J=11.7, 2.4 Hz, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.73 to 6.70 (m, 1H), 6.34 (s, 1H), 4.16 to 4.12 (m, 2H), 3.68 to 3.65 (m, 2H), 3.30 (s, 3H), 2.38 (s, 3H), 1.24 (s, 9H); MS LC-MS [M+H]+=534, RT=2.39 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:20]#[N:21])[CH2:19][CH2:18][CH2:17]2)=[C:12]([O:22][CH3:23])[CH:11]=1.O1C2C=CC=CC=2N=[C:25]1[C:33]1C=CC(C#N)=C(OC)C=1.BrCCCCCBr>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:20]#[N:21])[CH2:17][CH2:18][CH2:19][CH2:33][CH2:25]2)=[C:12]([O:22][CH3:23])[CH:11]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1C#N
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1C1(C#N)CCC1
Agent: BrCCCCCBr
Product: COc1cc(-c2nc3ccccc3o2)ccc1C1(C#N)CCCCC1

Procedure:
Utilizing the general procedure outlined for the synthesis of 1-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]cyclobutanecarbonitrile, 4-(1,3-benzoxazol-2-yl)-2-methoxybenzonitrile (250 mg, 0.95 mmol) was reacted with 1,5-dibromopentane (160 μL, 1.1 mmol) to afford the desired 1-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]cyclohexanecarbonitrile as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.83–7.75 (m, 3H), 7.59–7.56 (m, 1H) 7.45–7.43 (d, 1H), 7.38–7.34 (m, 2H), 4.04 (s, 3H), 2.41–2.38 (d, 2H), 1.92–1.15 (m, 8H). MS (ESI) 333 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.[Cl:22][CH2:23][CH2:24]Cl>O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][CH2:23][Cl:22])=[CH:6][CH:5]=1
Reactant: ClCCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(OCCCl)cc1
Temperature: 25 °C

Procedure:
4-hydroxybenzoic acid methyl ester (1.52 g, 10 mmol), anhydrous cesium carbonate (3.26 g, 10 mmol), 5 ml of dimethylsulfoxide that is dried over 4A molecular sieve, and 15 ml 1,2-dichloroethane are combined and stirred at about room temperature. After 15 hours the mixture is heated to reflux and more cesium carbonate (about 1 more equivalent). HPLC shows the ratio of product to bis alkylated biproduct to starting material is 93.1:6.2: non-detectable. The reaction mixture is cooled to room temperature and diluted with 30 ml of water. The mixture is stirred then the layers separated. The aqueous layer is extracted with 15 ml of methylene chloride and then the combined organics are filtered through sodium sulfate. The filtrate is concentrated in vacuo at about 60° C. to a yellow green oil which solidifies on cooling to give 2.00 g of product. (94.8%). HPLC.
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[NH:5][C:6]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:15][C:16]1[CH:17]=[N:18][C:19]2[CH:20](Br)[CH2:21][CH2:22][CH2:23][C:24]=2[CH:25]=1>O.CO>[CH3:15][C:16]1[CH:17]=[N:18][C:19]2[CH:20]([S:3][C:4]3[NH:5][C:6]4[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=4[N:8]=3)[CH2:21][CH2:22][CH2:23][C:24]=2[CH:25]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: Cc1cnc2c(c1)CCCC2Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2nc(SC3CCCc4cc(C)cnc43)[nH]c2c1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
2.80 Grams of sodium hydroxide was dissolved in 15 ml of water and 200 ml of methanol, then to this solution was added 10.63 g of 2-mercapto-5-methoxybenzimidazole and the reaction mixture was heated with stirring at 55° C. for 30 minutes. Next, 13.33 g of 3-methyl-8-bromo-5,6,7,8-tetrahydroquinoline was added to the reaction mixture, then the whole reaction mixture was stirred under heating for 2.5 hours. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, then to the residued thus obtained was added a small amount of 30% sodium hydroxide aqueous solution, and extracted with chloroform. The chloroform layer was washed wih an aqueous solution saturated with sodium chloride, then the extract was dried with anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane/methanol=100/1) to obtain 18.80 g of 3-methyl-8-(5-methoxy-2-benzimidazolyl)thio-5,6,7,8-tetrahydroquinoline as in the form of colorless caramel-like substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Product: Clc1cc(-c2ccccc2)nc(Cl)n1

Procedure:
As shown in Scheme 17, reaction of 2,4,6-trichloropyrimidine (8) with phenylboronic acid occurred at position 6 of the pyrimidine ring to give 2,4-dichloro-6-phenylpyrimidine (39) as the only isolated product. This is in contrast to the amine displacement reactions of Schemes 3 and 16, which occurred largely at the 4 position. Subsequent reaction with bridged C5-C9heterobicycle compound 2 occurred as expected at position 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH2:12][CH2:13][N:14]([C:17](OC(C)(C)C)=[O:18])[CH2:15][CH:16]=3)=[CH:10][C:3]=12.[N:34]1[CH:39]=CC=C[CH:35]=1.C1C([N+]([O-])=O)=CC=C([Cl-]C([O-])=O)C=1.Cl.CNC>C(Cl)Cl.FC(F)(F)C(O)=O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([N:34]([CH3:39])[CH3:35])=[O:18])[CH2:15][CH:16]=3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Cl)ccnc32)cc1
Reactant: c1ccncc1
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)N(C)C)CC3)cc3c(Cl)ccnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.8 %

Procedure:
Intermediate P-5-I (2 g, 6.94 mmol) was dissolved in CH2Cl2 (20 mL), to which trifluoroacetic acid (10 mL, excess) was added at 0° C. and the reaction mixture was stirred at room temperature for 2 h. Solvents were removed under reduced pressure and saturated NaHCO3 solution (50 mL) was added to it. Extraction was carried out using EtOAc (30 mL×2); the combined organic layers were washed with water (60 mL), brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide corresponding Boc-deprotected intermediate (1.6 g). It (0.5 g, 1.28 mmol) was dissolved in CH2Cl2 (10 mL) and cooled to 0° C. To this was added pyridine (1.0 mL, 12.8 mmol) and 4-nitrophenylchloroformate (1.29 g, 6.44 mmol) sequentially. The reaction mixture was stirred at room temperature for 3 h before solvent was removed under reduced pressure. To the residue obtained was added DMF (10 mL) and cooled to 0° C. To this reaction mixture, TEA (1.6 mL, 12.8 mmol) and dimethylaminehydrochloride (0.525 g, 6.44 mmol) were added and it was stirred at room temperature for 16 h. It was then diluted using water (30 mL) and extraction was carried out using EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (25% acetone in hexane) to provide the title compound P-5-II (0.25 g, 53% yield). LCMS: m/z; 459.2 (M+1)+.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[C:27]1([CH:33]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[N:34]2[C:42]3[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=3)[C:36](O)([C:44]3[C:52]([OH:53])=[CH:51][C:47]4[O:48][CH2:49][O:50][C:46]=4[CH:45]=3)[C:35]2=[O:55])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:56]1([CH:33]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:34]2[C:42]3[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=3)[CH:36]([C:44]3[C:52]([OH:53])=[CH:51][C:47]4[O:48][CH2:49][O:50][C:46]=4[CH:45]=3)[C:35]2=[O:55])[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: Cc1ccc2c(c1)C(O)(c1cc3c(cc1O)OCO3)C(=O)N2C(c1ccccc1)c1ccccc1
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: Cc1ccc2c(c1)C(c1cc3c(cc1O)OCO3)C(=O)N2C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-5-methyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (84%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.37-7.25 (m, 9H), 7.22-7.17 (m, 2H), 7.10 (s, 1H), 6.91 (s, 1H), 6.86 (d, 1H), 6.63 (s, 1H), 6.40 (s, 1H), 6.38 (d, 1H), 5.88 (ABq, 2H), 5.07 (s, 1H), 2.23 (s, 3H); MS (ES+) m/z 450.3 (M+1).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([CH2:13][C:14]1[C:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[N:16][O:17][C:18]=1[C:19](OCC)=[O:20])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(C)([O-])C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:15]2[C:14]3[CH:13]=[N:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:19]([OH:20])[C:18]=3[O:17][N:16]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccc(F)cc2)noc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2c(-c3ccc(F)cc3)noc2c1O
Temperature: -78 °C
Reaction time: 14 h
Yield: 69 %

Procedure:
Ethyl 4-(((2,4-dimethoxybenzyl)(2-ethoxy-2-oxoethyl)amino)methyl)-3-(4-fluorophenyl)isoxazole-5-carboxylate (8.7 g, 17.4 mmol) was dissolved in 150 mL of THF and cooled to −78° C. Potassium tert-butoxide solution (34.8 mL, 34.8 mmol, 1M in THF) was added dropwise, and the mixture was stirred for 14 hours, the cold bath allowed to evaporate spontaneously. The reaction mixture was quenched with 30 mL of 1M HCl and 200 mL of saturated ammonium chloride solution. The product was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated to give 7.54 g of crude oil. The crude intermediate was dissolved in 100 mL of CH2Cl2. Thionyl chloride (1.8 mL, 24.9 mmol) was added and within minutes a precipitate began to form. The reaction mixture was stirred for another hour and the mixture was filtered through a medium porosity funnel. The solid was rinsed twice with cold CH2Cl2 and dried under vacuum to give 3.63 g of the title compound. MS: (+) m/z 303.37 (M+1).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:10](=O)([O:13]C)[O:11][CH3:12].C[O-].[Na+].Cl>O.C1(C)C=CC=CC=1>[O:7]1[CH2:8][CH2:9][CH:4]([C:1](=[O:3])[CH2:2][C:10]([O:11][CH3:12])=[O:13])[CH2:5][CH2:6]1
Reactant: CC(=O)C1CCOCC1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)C1CCOCC1
Temperature: 7.5 °C
Yield: 80.5 %

Procedure:
In a flask made of glass having an inner volume of 500 ml and equipped with a stirring device, a thermometer, a dropping funnel and a distillation device were charged 35.0 g (273 mmol) of 4-acetyltetrahydropyran synthesized in the same manner as in Reference example 2, 280.0 g (3.1 mol) of dimethyl carbonate and 16.3 g (302 mmol) of sodium methoxide, and the mixture was reacted at 80 to 85° C. for 2 hours with distilling by-producing methanol off. After completion of the reaction, the reaction mixture was cooled to 5 to 10° C., and to the reaction mixture were added 175 ml of toluene, 55 ml (330 mmol) of 6 mol/l hydrochloric acid and 35 ml of water in this order. After the organic layer was separated, the aqueous layer was extracted twice with 70 ml of toluene. The organic layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (Fluent; hexane/ethyl acetate=1/1 (volume ratio)) to give 40.9 g (Isolation yield: 76%) of methyl 3-(4-tetrahydropyranyl)-3-oxopropanoate with a purity of 93.9% (analytical value by differential diffractometry) as a colorless liquid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][OH:9])[O:4]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[S:16]([O:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][O:9][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[O:4]1)([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1CC[C@H](CO)O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](COS(=O)(=O)c3ccc(C)cc3)O2)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a three-neck flask equipped with a thermometer, reflux condenser, mechanical stirrer, and dropping funnel a solution of 924 grams (7 moles) of cis-2,5-bis-(hydroxymethyl) tetrahydrofuran, represented by formula (I), in 900 ml of pyridine was placed and cooled at 5° C. A solution of 2669 grams (14 moles) of p-toluenesulfonyl chloride in 4 liters of pyridine was added slowly through the dropping funnel. The temperature during the addition was kept below 10°-15° C. After the addition of p-toluenesulfonyl chloride, the reaction mixture was stirred for 2 hours and then let stand at room temperature overnight. The reaction mixture was poured over ice-water and the product precipitated. The ditosylate, represented by formula (II), was filtered off and washed several times with water and dried. The product obtained had a melting point of 125°-126.5° C.